2. Academic Validation
  3. A potassium-chloride co-transporter promotes tumor progression and castration resistance of prostate cancer through m6A reader YTHDC1

A potassium-chloride co-transporter promotes tumor progression and castration resistance of prostate cancer through m6A reader YTHDC1

  • Cell Death Dis. 2023 Jan 6;14(1):7. doi: 10.1038/s41419-022-05544-8.
Shuai Yuan # 1,  Shao-Hua He # 1 2,  Lu-Yao Li 1 3,  Shu Xi 1 4,  Hong Weng 1 3,  Jin-Hui Zhang 1 4,  Dan-Qi Wang 1 3,  Meng-Meng Guo 1 4,  Haozhe Zhang 5,  Shuang-Ying Wang 1 3,  Dao-Jing Ming 1 4,  Meng-Yang Liu 1 3,  Hailiang Hu 6 7,  Xian-Tao Zeng 8 9
Affiliations

Affiliations

  • 1 Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 2 Precision Medicine Center, The Second People's Hospital of Huaihua, Huaihua, China.
  • 3 Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 4 School of Clinical Medicine, Henan University, Kaifeng, China.
  • 5 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 6 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China. [email protected].
  • 7 Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, China. [email protected].
  • 8 Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China. [email protected].
  • 9 Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 36609444 DOI: 10.1038/s41419-022-05544-8
Abstract

SLC12A5, a neuron-specific potassium-chloride co-transporter, has been reported to promote tumor progression, however, the underlying mechanism remains unclear. Here we report that SLC12A5 functions as an oncogene to promote tumor progression and castration resistance of prostate Cancer through the N6-methyladenosine (m6A) reader YTHDC1 and the transcription factor HOXB13. We have shown that the level of SLC12A5 was increased in prostate Cancer, in comparison to its normal counterparts, and further elevated in castration-resistant prostate Cancer (CRPC). The enhanced expression of SLC12A5 mRNA was associated with neuroendocrine prostate Cancer (NEPC) progression and poor survival in prostate Cancer. Furthermore, we demonstrated that SLC12A5 promoted the castration resistance development of prostate Cancer in addition to the cell proliferation and migration. Interestingly, SLC12A5 was detected in the cell nucleus and formed a complex with nuclear m6A reader YTHDC1, which in turn upregulated HOXB13 to promote the prostate Cancer progression. Therefore, our findings reveal a mechanism that how the potassium-chloride cotransporter SLC12A5 promotes the tumor progression and provide a therapeutic opportunity for prostate Cancer to apply the neurological disorder drug SLC12A5 inhibitors.

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